The present invention relates to a low dose pharmaceutical formulation for treating type 2 diabetes in drug naive patients, which includes metformin (preferably employed in reduced amounts compared to that employed in generally accepted medical practice) and another antidiabetic agent such as a sulfonyl urea, for example, glyburide, which formulation has at least substantially equivalent efficacy in treating type 2 diabetes as compared to prior art antidiabetic formulations containing metformin, but with substantially reduced side effects, and to a method for treating diabetes employing such formulations.
The biguanide antihyperglycemic agent metformin disclosed in U.S. Pat. No. 3,174,901 is currently marketed in the U.S. in the form of its hydrochloride salt (Glucophage(copyright)), Bristol-Myers Squibb Company).
The diagnosis and management of type 2 diabetes mellitus is rapidly undergoing progressive changes. It is now widely accepted that glycemic control makes a difference. The goal of diabetes therapy today is to achieve and maintain as near normal glycemia as possible to prevent the long-term microvascular and macrovascular complications of an elevated blood glucose. The diagnosis of diabetes has undergone significant changes as evidenced by the new ADA diagnostic and classification guidelines. Oral therapeutic options for the treatment of type 2 diabetes mellitus, until recently, have been severely limited. Prior to 1995, sulfonyl ureas had been the mainstay of oral diabetes agents in the United States. Sulfonyl ureas target one mechanism of hyperglycemia by augmenting insulin secretion from the beta cell. Since 1995, three new classes of agents have been added to the anti-diabetes armamentarium for the management of hyperglycemia. Metformin, a biguanide, targets additional mechanisms of hyperglycemia by inhibiting hepatic glucose production and enhancing peripheral glucose uptake and thereby reduce insulin resistance; thiazolidinediones such as troglitazone, rosiglitazone and pioglitazone decrease peripheral insulin resistance; and alpha-glucosidase inhibitors such as acarbose and miglitol help control postprandial glucose excursion by delaying absorption of dietary carbohydrate. These agents are all indicated as monotherapy and some are indicated for use in combination therapy, generally, after monotherapy has been found to be inadequate.
In 1995, metformin was added to sulfonyl urea therapy n patients who had not achieved glycemic control with sulfonyl urea monotherapy and the two agents were found to have a remarkable effect on glycemic control or lowering of hemoglobin-A1c. The different mechanisms of action in targeting hyperglycemia are complimentary and make combination use attractive and a rational course of action. Prescription data reveals approximately 60% of metformin use is in combination with a sulfonyl urea.
Examples of combinations of metformin and the sulfonyl urea glyburide (also referred to as glibenclamide) are disclosed in the following references.
(1) WO 97/17975 published May 22, 1997, (Barelli et al, Istituto Gentili S.P.A.) (hereinafter Barelli et al) discloses a combination of glibenclamide and metformin in a 1:100 weight ratio, so as to allow a daily dosage of 15 mg glibenclamide and 1500 mg metformin, used for the onset of diabetes to the most severe cases, particular in cases of secondary failure to a combination of glibenclamide-metformin HCl in a weight ratio higher than 1:100.
(2) Vigneri et al, Treatment of NIDDM Patients with Secondary Failure to Glyburide: Comparison of the Addition of Either Metformin or Bed-Time NPH Insulin to Glyburide, Diabete and Metabolisme, 1991, 17, 232-234, disclose use of a combination of 1.5 g/day metformin and 15 mg/day glyburide to treat NIDDM patients with secondary failure to 15 mg/day glyburide.
(3) Higginbotham et al, Double-Blind Trial of Metformin in the Therapy of Non-Ketotic Diabetes, The Medical Journal of Australia, Aug. 11, 1979, 154-156, discloses treatment of diabetic patients, who were already receiving from 10 mg to 20 mg per day of glibenclamide, with 500 mg metformin twice a day. Higginbotham et al conclude xe2x80x9cthat in selected diabetics whose condition is inadequately controlled with sulphonylurea therapy, significant improvement in diabetic control can be obtained by the addition of metformin in a low dose of 500 mg twice a day.xe2x80x9d
(4) U.S. application Ser. No. 09/353,141, filed Jul. 14, 1999 (based on European application No. 98401781.4, filed Jul. 15, 1998) discloses formulations containing metformin and glyburide where the glyburide is of a particular particle size as described hereinafter.
References which disclose combinations of metformin and glipizide include the following:
(1) Combination of glipizide/metformin treatment reduces low density lipoprotein binding to arterial proteglycans in DIDDM, Edwards et al, Diabetes, (46, Suppl. 1, 45A, 1997).
(2) Combination of glipizide/metformin normalizes glucose and improves insulin sensitivity in hyperinsulinemia moderately well controlled. Cefalu et al, Diabetes, (45, Suppl. 2, 201A, 1996).
(3) Effects of combination of glipizide/metformin treatment on oxidizability of LDL in NIDDM, Crouse et al, Circulation, (94, No. 8, Suppl., 1508, 1996).
(4) Insulin sensitivity is improved after glipizide monotherapy and combination with metformin, Cefalu et al, Diabetologia, (39, Suppl. 1, A231, 1996).
(5) Combined Metforminxe2x80x94Sulfonyl urea Treatment of Patients with NIDDM in Fair to Poor Glycemic Control, Reaven et al, J. Clin. Endocrinol. Metab. (74, No. 5, 1020-26, 1992).
(6) Combination of Glipizide/Metformin Treatment in NIDDM, Hollenbeck et al, Diabetes, (39, Suppl. 1, 108A, 1990).
(7) Oral Antidiabetic Combination Therapy with Sulfonyl ureas and Metformin, Haupt et al, Med. Welt. (40, No. 5, 118-23, 1989).
(8) Variation of the lipemic pattern in diabetic subjects after treatment with a combination of glipizide and metformin, Ferlito et al, PROGR. MED. (Roma) 31/6 (289-301) 1975.
(9) Results with a combination of glipizide and dimethylbiguanide in 40 cases of diabetes, Parodi et al, GAZZ. MED. ITAL. 132/5 (226-235) 1973.
Other combinations of metformin and another antidiabetic agent are disclosed in the following references.
(1) U.S. Pat. No. 5,631,224 to Efendic et al discloses a combination of metformin with GLP-1(7-36) amide or GLP-1(7-37) or a fragment thereof.
(2) WO 98/57634 (SKB) discloses a method for treating diabetes employing a combination of a thiazolidenedione and metformin. The thiazolidenedione may be troglitazone, ciglitazone, pioglitazone or englitazone, and may be employed in dosages of 2 to 12 mg per day while the metformin may be employed in daily dosages xe2x80x9cof up to 3000 mg per day, in unit doses of 500 mg (for example, 2 to 3 times per day) or 850 mg (2 times per day), one example of a dosage for metformin is 500 mg building to 5 times per day.xe2x80x9d
(3) EP 0749751A2 (Takeda) discloses a combination of a thiazolidenedione insulin sensitivity enhancer (such as pioglitazone) and metformin.
None of the above references suggests employing diabetic combinations containing metformin for first line treatment of drug naive patients.
Several fixed combinations of metformin and glyburide (glibenclamide) are presently being marketed outside the U.S. These include (1) combinations of 400 mg metformin/2.5 mg glibenclamide (Boehringer""s Bi-Euglucon in Argentina, and Bi-Euglicon M in Italy; Guidotti/Menarini""s Glibomet in the Dominican Republic and Italy; HMR""s Normell in Greece and Hoechst""s Suguan-M in Italy; Sun Pharma""s Glucored in India; Monsanto""s (Searle""s) Benclamet in India; Guidotti""s Globate in Liban; Berlin Chemie/Menarini""s Glibomet in the Slovak Rep., and Roche""s Bi-Euglucon in Uruguay); (2) combinations of 500 mg metformin/5 mg glibenclamide (Sun Pharma""s Glucored in India; Monsanto""s (Searle""s) Benclamet in India, USV""s Duotrol in India; and Lakeside""s (Roche) Bi-Euglucon M5 in Mexico); (3) combinations of 500 mg metformin/2.5 mg glibenclamide (Molteni""s Glucomide in Italy, Lakeside""s (Roche) Bi-Euglucon M in Mexico and Szabo""s Dublex in Uruguay); and (4) 1 g metformin/5 mg glibenclamide (Silanes Sil-Norboral in Mexico).
The labelling for Glucophage(copyright) (Bristol-Myers Squibb""s metformin), in the Physicians"" Desk Reference 1999, under xe2x80x9cIndications and Usexe2x80x9d, indicates that Glucophage may be used concomitantly with a sulfonylurea. It is further indicated under xe2x80x9cDosage and Administrationxe2x80x9d xe2x80x9cConcomitant Glucophage and Oral Sulfonylurea Therapyxe2x80x9d that xe2x80x9cIf patients have not responded to four weeks of the maximum dose of Glucophage monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing Glucophage at the maximum dose . . . With concomitant Glucophase and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. However, attempts should be made to identify the maximum effective dose of each drug to achieve this goal.xe2x80x9d The recommended dosing schedule for Glucophage is a starting dose of 500 mg twice a day or 850 mg once a day with dosage increases in increments of 500 mg weekly or 850 mg every 2 weeks up to a total of 2000 mg per day.
Package inserts for Bi-Euglucon M and Suguan M in Italy (400 mg metformin/2.5 mg glibenclamide) indicate that these drug combinations are used in cases of primary or secondary resistance to sulfonyl ureas [that is as second or third line therapy] and that a dosage of xc2xd tablet per day increasing xc2xd tablet at a time according to glycemic variations up to 4 tablets per day are employed.
Package inserts for Glibomet (400 mg metformin/2.5 mg glibenclamide) and Glucomide (500 mg metformin/2.5 mg glibenclamide) in Italy indicate that these drug combinations are used for treating type 2 diabetes which is non-controllable or cannot be controlled with only diet or with diet and sulfonyl urea [that is as first line therapy of second line therapy].
The package insert for Glibomet in Italy indicates a daily dosage of 2 tablets, that is 800 mg metformin and 5 mg glibenclamide, up to 2 grams metformin. The package insert for Glucomide in Italy indicates a daily dosage of 2 capsules, that is 1000 mg metformin up to 2 grams metformin, and 5 mg glibenclamide.
In accordance with the present invention, a low dose pharmaceutical formulation is provided which includes a combination of metformin and at least one other antidiabetic agent, which preferably is glyburide, which combination provides at least substantially equivalent efficacy in treating diabetes in drug naive patients (in first line therapy) as do combinations of metformin and the other antidiabetic agent employed in substantially higher dosages as prescribed in generally accepted medical practice for first line therapy in treating diabetes. However, use of the low dose pharmaceutical formulation of the invention results in substantially reduced side effects as compared to the same combination employed in the higher doses as generally prescribed.
It is to be understood that the low dose formulation of the invention will include a xe2x80x9clow dosexe2x80x9d of at least one of the active antidiabetes drug components, that is a lower dosage than the dosage for such drug prescribed in generally accepted medical practice in first line therapy of treating diabetes. Thus, the above low dose pharmaceutical formulation will include a low dose of metformin as defined hereinafter, or a low dose of other antidiabetic agent as defined hereinafter, or a low dose of each of metformin and other antidiabetic agent as defined hereinafter.
In accordance with the present invention, efficacy in first line therapy in treating diabetes in drug naive patients is achieved employing the low dose pharmaceutical formulation of the invention wherein the daily dosage of the metformin may be employed in a daily dosage prescribed in generally accepted medical practice for first line therapy in treating diabetes, and is preferably within the range which comprises a starting daily dosage as low as about one-fifth of the starting daily dosage of metformin employed in generally accepted medical practice for first line therapy for treating diabetes, up to a daily maintenance dosage of about two-thirds of the daily maintenance dosage of metformin employed in generally accepted medical practice for first line therapy for treating diabetes.
The low dose pharmaceutical formulation of the invention will more preferably contain metformin where the daily dosage of the metformin is within the range which comprises a starting daily dosage as low as about 25% up to about 60% of the starting daily dosage of metformin employed in generally accepted medical practice for first line therapy for treating diabetes, up to a daily maintenance dosage of from about 40 to about 60% of the maintenance dosage employed in generally accepted medical practice for first line therapy for treating diabetes.
Thus, in effect, the low dose pharmaceutical formulation of the invention will be employed in first line therapy in a daily dosage to provide less than about 800 mg metformin per day, preferably no more than about 750 mg metformin per day, more preferably no more than about 600 mg metformin per day, and a minimum (starting dosage) of about 160 to about 225 mg per day, in single or divided doses of one to four tablets daily.
The other antidiabetic agent (which preferably is a sulfonyl urea, preferably glyburide) may be employed in a daily dosage prescribed in generally accepted medical practice for first line therapy in treating diabetes, and is preferably employed in a daily dosage within the range which comprises a starting daily dosage as low as about one-tenth of the starting daily dosage of other antidiabetic agent employed in generally accepted medical practice for first line therapy for treating diabetes, up to a daily maintenance dosage of about two-thirds of the daily maintenance dosage of other antidiabetic agent employed in generally accepted medical practice for first line therapy for treating diabetes.
The other antidiabetic agent will preferably be employed in a daily dosage within the range which comprises a starting daily dosage as low as about 20% up to about 60% of the starting daily dosage of such other antidiabetic agent employed in generally accepted medical practice for first line therapy for treating diabetes, up to a daily maintenance dosage of about 40 to about 60% of the daily maintenance dosage of such other antidiabetic agent employed in generally accepted medical practice for first line therapy for treating diabetes.
The above daily dosage of the other antidiabetic agnet (which preferably is glyburide) includes starting daily dosages of such antidiabetic agent (for example 0.1 to 1.5 mg glyburide) up to a maximum maintenance daily dosage as prescribed in generally accepted medical practice for first line therapy in treating diabetes. In the case of glyburide, the daily dosage will preferably be up to two-thirds the daily dosage as prescribed in generally accepted medical practice for first line therapy in treating diabetes that is up to about 4.5 mg, preferably up to about 3.75 mg glyburide, per day, in single or divided doses of one to four tablets daily.
The term xe2x80x9clow dose combinationxe2x80x9d, xe2x80x9clow dose formulationxe2x80x9d or xe2x80x9clow dose pharmaceutical formulationxe2x80x9d as employed herein, in a preferred formulation of the invention, refers to a formulation which includes metformin in a starting daily dosage of as low as about one-fifth the starting daily dosage of metformin prescribed in generally accepted medical practice for first line therapy in treating diabetes up to about two-thirds the maintenance daily dosage of metformin prescribed in generally accepted medical practice for first line therapy in treating diabetes. The above daily dosage of metformin incudes starting daily dosages of metformin (for example as low as 160 mg) and dosages of metformin titrated up to a maximum maintenance dosage of less than about 800 mg metformin per day, preferably less than about 750 mg per day; and other antidiabetic agent employed in amounts set out herein.
Until now, combinations of metformin and another antidiabetic drug, for example, a sulfonyl urea, such as glyburide, have normally been used with few exceptions, as second line therapy in treating type 2 diabetes. Generally accepted medical practice daily dosages for such second line therapy employing fixed combinations of metformin and glyburide range from 3 to 4 tablets containing 400 to 500 mg metformin and 2 to 2.5 mg glyburide, or about 1200 to 2000 mg metformin and 6 to 10 mg glyburide, daily.
As indicated above with respect to Glibomet and Glucomide (fixed combinations of metformin and glyburide) marketed in Italy, these combinations may be employed as first line therapy (drug naive patients) in a daily dosage of 800 to 1000 mg up to 2 grams metformin and 5 mg glibenclamide (glyburide). This daily dosage is referred to herein as xe2x80x9cdosages prescribed in generally accepted medical practice for first line therapy in treating diabetesxe2x80x9d or as dosages of xe2x80x9cprior art combinationsxe2x80x9d or xe2x80x9cprior art daily dosages.xe2x80x9d
The above dosages may be included within the term xe2x80x9cdosages as prescribed in generally accepted medical practice for first line therapy in treating diabetes.xe2x80x9d
As indicated above with respect to Boehringer""s Bi-Euglucon M and Hoechst""s Suguan M (fixed combinations of metformin and glibenclamide) marketed in Italy, these combinations are employed as second line therapy in a daily dosage starting at xc2xd tablet, that is, 200 mg metformin and 1.25 mg glibenclamide. The initial or starting low doses are employed to determine if the patient can tolerate the drugs and these doses are gradually titrated upwardly xc2xd tablet at a time up to 4 tablets per day until an efficacious dosage is achieved. The initial or starting daily dosage of xc2xd tablet or 200 mg metformin and 1.25 mg glibenclamide is not considered by Boehringer and Hoechst and physicians prescribing these drugs as xe2x80x9cdosages as prescribed in generally accepted medical practice for treating diabetes.xe2x80x9d
Surprisingly, it has been found that use of the combination of metformin and glyburide in accordance with the present invention affords the following benefits. The low dose metformin is an insulin sensitizer and decreases insulin resistance at the liver, muscle and pancreas. The low dose metformin-glyburide combination acts on the pancreas as a glucose sensitizer; it decreases glucose toxicity at the pancreas and improves function of the pancreas.
In addition, in accordance with the present invention, a method is provided for treating diabetes, especially type 2 diabetes, in a drug naive human patient, which includes the step of administering to a drug naive human patient in need of treatment, as first line therapy, a therapeutically effective low dose pharmaceutical formulation of the invention which includes a combination of metformin and at least one other antidiabetic agent (preferably glyburide), in dosages as described herein, which combination provides at least substantially equivalent efficacy in treating diabetes in drug naive patients as do combinations of metformin and said other antidiabetic agent employed in dosages prescribed in generally accepted medical practice for first line therapy treating diabetes, but with substantially reduced side effects.
In addition, in accordance with the present invention, a method is provided for decreasing fasting plasma glucose, decreasing insulin resistance, decreasing hemoglobin A1c, increasing post-prandial insulin and/or decreasing post-prandial glucose excursion in a human diabetic patient, which includes the step of administering to a human patient the low dose pharmaceutical formulation of the invention which includes a combination of metformin/other antidiabetic agent, preferably glyburide. It is preferred that the low dose pharmaceutical formulation be administered as first line therapy and that the human patient be a drug naive patient.
In carrying out the method of the invention employing the preferred low dose pharmaceutical formulation of the invention containing metformin and glyburide, to treat drug naive patients for diabetes, it has been found that the efficacy in treating drug naive patients is at least substantially equivalent and incidence of side effects (gastrointestinal side effects and hypoglycemia) is surprisingly significantly and substantially reduced as compared to patients on prior art daily dosages of metformin and glyburide (that is in dosages prescribed in generally accepted medical practice for treating diabetes). Thus, while efficacy in treating drug naive patients as measured by decrease in hemoglobin A1c from baseline over time, decrease in fasting plasma glucose (FPG), increase in post-prandial insulin levels, and decrease in post-prandial glucose (PPG) excursion, are essentially substantially equivalent in the above-described patients when employing the low dose pharmaceutical formulation of the invention and the prior art daily dosages or prior art combinations, incidence of hypoglycemia in drug naive patients treated with prior art daily dosages is more than 3 times greater than in patients treated with the low dose pharmaceutical formulation of the invention, and incidence of gastrointestinal side effects in drug naive patients treated with prior art daily dosages is more than 20% greater than patients treated with the low dose pharmaceutical formulation of the invention.
Preferred daily dosages of a combination of metformin and glyburide will be in the range from about 175 to about 600 mg metformin, more preferably from about 200 to about 500 mg metformin, still more preferably from about 250 to about 400 mg metformin, and from about 0.5 to about 4.5 mg glyburide, preferably from about 0.625 to about 3.75 mg glyburide, and more preferably from about 1 to about 1.5 mg glyburide.
The term xe2x80x9cdiabetesxe2x80x9d as employed herein, refers to type 2 (or Type II) diabetes or non-insulin dependent diabetes mellitus (NIDDM).
The term xe2x80x9cmetforminxe2x80x9d as employed herein refers to metformin or a pharmaceutically acceptable salt thereof such as the hydrochloride salt, the metformin (2:1) fumarate salt, and the metformin (2:1) succinate salt as disclosed in U.S. application Ser. No. 09/262,526 filed Mar. 4, 1999, the hydrobromide salt, the p-chlorophenoxy acetate or the embonate, and other known metformin salts of mono and dibasic carboxylic acids including those disclosed in U.S. Pat. No. 3,174,901, all of which salts are collectively referred to as metformin. It is preferred that the metformin employed herein be the metformin hydrochloride salt, namely, that marketed as Glucophage(copyright) (trademark of Bristol-Myers Squibb Company).
The term xe2x80x9csubstantially reduced side effectsxe2x80x9d as employed herein refers to reduced incidence of hypoglycemia and gastrointestinal adverse events including diarrhea, nausea/vomiting and/or abdominal pain, occurring with use of the low dose pharmaceutical formulation of the invention in drug naive patients as compared to patients on the same active components in the pharmaceutical formulation of the invention but at higher dosages as prescribed in generally accepted medical practice for treating diabetes.
The term xe2x80x9cat least substantially equivalent efficacyxe2x80x9d in treating type 2 diabetes as employed herein refers to the effectiveness of the low dose pharmaceutical formulation of the invention in treating drug naive patients to reduce and/or maintain hemoglobin A1c (glycosylated hemoglobin) at 7% or less, to decrease insulin resistance (by increasing post-prandial insulin level) and/or to decrease post-prandial glucose (PPG) excursion, as compared to patients treated with the same active components in the pharmaceutical formulation of the invention but at higher dosages as prescribed in generally accepted medical practice for treating diabetes.
The term xe2x80x9cpost-prandial excursionxe2x80x9d as employed herein refers to the difference between post-prandial glucose (PPG) and fasting plasma glucose (FPG).
The low dose pharmaceutical formulation of the invention will contain metformin used in combination with another antidiabetic agent (also referred to herein as xe2x80x9canother antihyperglycemic agentxe2x80x9d) which may be administered orally in the same dosage form or in separate oral dosage forms or by injection.
The other antidiabetic agent may be one or more of the following: a sulfonyl urea, a glucosidase inhibitor, a thiazolidinedione, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin, a PPAR xcex1/xcex3 dual agonist, a meglitinide, and/or an aP2 inhibitor.
It is believed that the use of metformin in combination with another antidiabetic agent in accordance with the present invention produces antihyperglycemic results greater than that possible from each of these medicaments alone and greater than the combined additive anti-hyperglycemic effects produced by these medicaments.
The other antidiabetic agent will preferably be a sulfonyl urea such as glyburide (also known as glibenclamide), glimepiride (disclosed in U.S. Pat. No. 4,379,785), glipyride, glipizide, gliclazide or chlorpropamide, and/or other known sulfonyl ureas or other antihyperglycemic agents which act on the ATP-dependent channel of the xcex2-cells, with glyburide being most preferred. The sulfonyl urea may be administered in the same oral dosage form with metformin or a separate oral dosage form.
Metformin will be employed in a weight ratio to the sulfonyl urea in the range from about 1000:1 to about 10:1, preferably from about 400:1 to about 100:1, more preferably from about 250:1 to about 150:1, and optimally about 200:1.
The oral antidiabetic agent may also be a glucosidase inhibitor such as acarbose (disclosed in U.S. Pat. No. 4,904,769), vaglibose, miglitol (disclosed in U.S. Pat. No. 4,639,436), which may be administered in a separate oral dosage form or the same dosage form with metformin.
Metformin will be employed in a weight ratio to the glucosidase inhibitor within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 50:1.
The other antidiabetic agent may be a meglitinide, for example, repaglinide (Prondin(copyright), NovoNordisk) or nataglinide (Starlex(copyright), Novartis), which may be administered in a separate oral dosage form or the same oral dosage form with metformin.
Metformin will be employed in a weight ratio to the meglitinide within the range of from about 0.01 to about 500:1, preferably from about 0.5:1 to about 300:1.
Metformin may be employed in combination with a thiazolidinedione oral antidiabetic agent or other insulin sensitizers (which has an insulin sensitivity effect in NIDDM patients) such as troglitazone (Warner-Labert""s Rezulin(copyright), disclosed in U.S. Pat. No. 4,572,912), rosiglitazone (SKB-Avandia(copyright)), pioglitazone (Takeda-Lilly-Actos(copyright)), Mitsubishi""s MCC-555 (disclosed in U.S. Pat. No. 5,594,016), Glaxo-Welcome""s GL-262570, englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer), which may be administered in a separate oral dosage form or the same oral dosage form with metformin.
Metformin will be employed in a weight ratio to the thiazolidinedione in an amount within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 5:1.
The thiazolidinedione in amounts of less than about 150 mg oral antidiabetic agent may be incorporated in a single tablet with metformin.
The other antidiabetic agent may be an aP2 inhibitor such as disclosed in U.S. Provisional Applications No. 60/100,677 filed Sep. 17, 1998, and No. 60/127,745 filed Apr. 5, 1999, the disclosures of which are incorporated herein by reference. Doses employed are as set out in the above applications.
Metformin will be employed in a weight ratio to the aP2 inhibitor in an amount within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 2:1. The aP2 inhibitor and metformin may be incorporated in the same or separate dosage forms.
Metformin may also be employed in combination with a non-oral antihyperglycemic agent such as insulin or with glucagon-like peptide-1 (GLP-1) such as GLP-1(1-36) amide, GLP-1(7-36) amide, GLP-1(7-37) (as disclosed in U.S. Pat. No. 5,614,492 to Habener, the disclosure of which is incorporated herein by reference), which may be administered via injection, or by transdermal or buccal devices.
Where present, the sulfonyl urea, such as glyburide, glimepiride, glipyride, glipizide, chlorpropamide or gliclazide, the thiazolidenedione, such as troglitazone, rosiglitazone or pioglitazone, the glucosidase inhibitor acarbose or miglitol, the meglitinide such as repaglinide or nataglinide, or insulin may be employed in formulations as described above and in formulations, amounts and dosing as indicated in the Physicians"" Desk Reference.
Where present, GLP-1 peptides may be administered in oral buccal formulations, by nasal administration or parenterally as described in U.S. Pat. Nos. 5,346,701 (TheraTech), 5,614,492 and 5,631,224 which are incorporated herein by reference.
Metformin may be employed in combination with another antidiabetic agent which may be a PPAR xcex1/xcex3 dual agonist such as an N-benzyldioxothiazolidylbenzamide derivative such as disclosed in WO 96/38428 such as 5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-[4-(trifluoromethyl)benzyl]benzamide (KRP-297), WO 98/05531 (Ligand Pharmaceuticals, Inc.) which discloses 2-(4-[2,4-difluorophenyl]-1-heptylureido)ethyl]phenoxy)-2methylbutyric acid, and WO 97/25042 and WO96/04260 (SKB) which disclose benzoxazole and pyridine derivatives of the structure 
or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein R0 represents 2-benzoxazolyl or 2-pyridyl and R1 represents CH2OCH3 or CF3, such as (S) -3-[4-[2-[N-(2-benzoxazolyl) -N-methylamino)ethoxy]phenyl]-2-(2-methoxy-ethoxy)propanoic acid; or (S)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]-ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoic acid; or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof. Dosages employed are as set out in the above references.
Metformin will be employed in a weight ratio to the PPAR xcex1/xcex3 dual agonist within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 5:1.
Where metformin is employed in combination with the PPAR xcex1/xcex3 dual agonist, the combination may be employed in an oral dosage form such as a tablet or capsule as will be apparent to one skilled in the art.
Preferred are low dose combinations of metformin and glyburide and optionally an insulin sensitizer such as a glitazone, for example, rosiglitazone, pioglitazone or troglitazone.
In carrying out the present invention, a low dose pharmaceutical formulation or composition will be employed containing metformin and at least one other antidiabetic agent in association with a pharmaceutical vehicle or diluent. The low dose pharmaceutical formulation can be formulated employing conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the mode of desired administration. The low dose pharmaceutical formulation of the invention can be administered to mammalian species including humans, monkeys, dogs, etc., by an oral route, for example, in the form of tablets, capsules, granules or powders, or it can be administered by a parenteral route in the form of injectable preparations. The dose for drug naive patients is as described above, which can be administered in a single dose or in the form of individual doses from 1-4 times per day.
The above dosage forms may also include the necessary physiologically acceptable carrier material, excipient, lubricant, buffer, antibacterial, bulking agent (such as mannitol), anti-oxidants (ascorbic acid or sodium bisulfite) or the like.
The dose administered must be carefully adjusted according to the age, weight, and condition of the patient, as well as the route of administration, dosage form and regimen, and the desired result.
The combination of the metformin or salt thereof and the other antidiabetic agent may be formulated separately or, where possible, in a single formulation employing conventional formulation procedures.
The various formulations of the invention may optionally include one or more fillers or excipients in an amount within the range of from about 0 to about 90% by weight and preferably from about 1 to about 80% by weight such as lactose, sugar, corn starch, modified corn starch, mannitol, sorbitol, inorganic salts such as calcium carbonate and/or cellulose derivatives such as wood cellulose and microcrystalline cellulose.
One or more binders may be present in addition to or in lieu of the fillers in an amount within the range of from about 0 to about 35% and preferably from about 0.5 to about 30% by weight of the composition. Examples of such binders which are suitable for use herein include polyvinylpyrrolidone (molecular weight ranging from about 5000 to about 80,000 and preferably about 40,000), lactose, starches such as corn starch, modified corn starch, sugars, gum acacia and the like as well as a wax binder in finely powdered form (less than 500 microns) such as carnauba wax, paraffin, spermaceti, polyethylenes or microcrystalline wax.
Where the composition is to be in the form of a tablet, it will include one or more tableting lubricants in an amount within the range of from about 0.2 to about 8% and preferably from about 0.5 to about 2% by weight of the composition, such as magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax and the like. Other conventional ingredients which may optionally be present include preservatives, stabilizers, anti-adherents or silica flow conditioners or glidants, such as Syloid brand silicon dioxide as well as FDandC colors.
Tablets of the invention may also include a coating layer which may comprise from 0 to about 15% by weight of the tablet composition. The coating layer which is applied over the outer solid phase containing particles of inner solid phase embedded therein may comprise any conventional coating formulations and will include one or more film-formers or binders, such as a hydrophilic polymer like hydroxypropylmethylcellulose , and/or a hydrophobic polymer like methacrylic acid esters neutral polymer, ethyl cellulose, cellulose acetate, polyvinyl alcohol-maleic anhydride copolymers, xcex2-pinene polymers, glyceryl esters of wood resins and the like and one or more plasticizers, such as triethyl citrate, diethyl phthalate, propylene glycol, glycerin, butyl phthalate, castor oil and the like. Both core tablets as well as coating formulations may contain aluminum lakes to provide color.
The film formers are applied from a solvent system containing one or more solvents including water, alcohols like methyl alcohol, ethyl alcohol or isopropyl alcohol, ketones like acetone, or ethylmethyl ketone, chlorinated hydrocarbons like methylene chloride, dichloroethane, and l,l,l-trichloroethane.
Where a color is employed, the color will be applied together with the film former, plasticizer and solvent compositions.
The finished dosage form is either a compressed tablet or a hard gelatin capsule, preferably a tablet. The tablet may be optionally film coated. The total amount of drug per dosage unit would be such as to offer a dosage form of convenient size for patients.
Where the low dose pharmaceutical formulation of the invention includes a combination of metformin and glyburide, the formulation will be administered so as to provide from about 55 to about 500 mg metformin one to four times daily, with a minimum of about 160 mg metformin daily and a maximum of less than about 800 mg, preferably up to about 750 mg metformin daily. The glyburide will preferably be administered in an amount from about 0.5 to about 3.75 mg one to four times daily, with a maximum of up to about 4.5 mg daily.
The preferred low dose pharmaceutical formulation of the invention is comprised of metformin and glyburide and is employed as initial therapy that is as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.
The ADA recommends a treatment goal of HbA1c less than 7% (ADA. Diabetes Care 21 [Suppl. 1]: S23-S31, 1998) in order to reduce the risk of complications of type 2 diabetes mellitus, including coronary heart disease and microvascular complications.
Dosage of the preferred metformin-glyburide combination of the invention must be individualized on the basis of both effectiveness and tolerance. It is preferably given with meals and should be started at a low dose, with gradual dose escalation. Ideally, the response to therapy should be evaluated using HbA1c (glycosylated hemoglobin) which is a better indicator of long-term glycemic control than FPG alone. The therapeutic goal in all patients with type 2 diabetes mellitus should be to improve glycemic control, including FPG, postprandial glucose and HbA1c levels, to normal or as near normal as possible. Patients should be titrated to achieve the ADA goal of HbA1c greater than 7% following the dosing recommendations up to the maximum recommended dose. (ADA. Diabetes Care 21 [Suppl. 1]: S23-S32, 1998).
As initial therapy, the preferred starting dose of the metformin-glyburide combination of the invention is 250/1.25 mg once a day, given with a meal. For patients with a baseline HbA1c greater than 9% or a fasting glucose  greater than 200 mg/dL, a recommended starting dose of 250/1.25 mg twice daily with the morning and evening meal may be preferred. Dosage increases should preferably be made in increments of 250/1.25 mg, every 2 weeks, up to the minimum effective dose necessary to achieve adequate glycemic control. For those patients requiring additional glycemic control, the 250 mg/1.25 mg dosage may be switched to 500/2.5 mg. However, as indicated, the preferred maximum daily dosage for metformin is 600 to 750 mg and the preferred maximum daily dosage for glyburide is 3.75 mg.
The low dose pharmaceutical formulation containing the metformin-glyburide combination, in accordance with the present invention, will preferably be formulated according to the teachings disclosed in U.S. application Ser. No. 09/353,141, filed Jul. 14, 1999, which claims priority from European application No. 98401781.4 filed Jul. 15, 1998, which U.S. application is incorporated herein by reference.
The preferred low dose metformin-glyburide formulation is set out below.
The especially preferred low dose metformin-glyburide formulations are as follows:
The low dose pharmaceutical formulation of the invention in the form of a solid oral form such as a tablet, will preferably contain a combination of metformin and glyburide in which the size of the glyburide is such that at most 10% of the particles are less than 2 xcexcm and at most 10% of the particles are greater than 60 xcexcm. Preferably, the size of the glyburide is such that at most 10 of the particles are less than 3 xcexcm and at most 10% of the particles are greater than 40 xcexcm. This specific size range of glyburide may be obtained by sieving or air jet milling.
In a second embodiment, the low dose solid oral dosage form of the invention will contain a combination of metformin and glyburide in which the size of glyburide is such that at most 25% of the particles are less than 11 xcexcm and at most 25% of the particles are greater than 46 xcexcm.
Preferably, 50% of particles are less than 23 xcexcm.
Most preferred are a combination of metformin and glyburide, where the glyburide has a particle size distribution of about 25% undersize value not more than 6 xcexcm, about 50% undersize value 7 to 10 xcexcm and about 75% undersize value not more than 23 xcexcm.
The low dose pharmaceutical formulation of the invention in the form of a tablet may be obtained by a process which includes the steps of
a) forming granules by wet granulation of a mixture of metformin and glyburide
b) blending the granules with a tabletting aid and diluent, and
c) tabletting the blend thus obtained into tablets.
The mixture used for forming the granules includes a granulating binder. The granulating binder is preferably a polyvinylpyrrolidone such as, for example, a polyvinylpyrrolidone having a molecular weight of 45,000. The polyvinylpyrrolidone may be used in a proportion of 2 to 4% by weight with respect to the final tablet.
After the granulating step, the granules may be sieved and dried.
The granules are then blended with a diluent and tableting aid. The diluent may be a conventional filler usually used for making tablets, such as microcrystalline cellulose. The tabletting aid may be a conventional material, such as magnesium stearate.
The tablets thus obtained may then optionally be coated with a hydrophilic cellulose polymer and talc. The hydrophilic cellulose polymer is preferably 2-hydroxypropyl methylcellulose.